9nu1
Uromodulin filament lattice interface from human urine
Structural highlights
DiseaseUROM_HUMAN UMOD-related autosomal dominant tubulointerstitial kidney disease. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionUROM_HUMAN Functions in biogenesis and organization of the apical membrane of epithelial cells of the thick ascending limb of Henle's loop (TALH), where it promotes formation of complex filamentous gel-like structure that may play a role in the water barrier permeability (Probable). May serve as a receptor for binding and endocytosis of cytokines (IL-1, IL-2) and TNF (PubMed:3498215). Facilitates neutrophil migration across renal epithelia (PubMed:20798515).[1] [2] In the urine, may contribute to colloid osmotic pressure, retards passage of positively charged electrolytes, prevents urinary tract infection and inhibits formation of liquid containing supersaturated salts and subsequent formation of salt crystals.[UniProtKB:Q91X17] Publication Abstract from PubMedUromodulin (UMOD), the most abundant protein in human urine, is essential for kidney function and urinary tract health. UMOD forms filaments that bind to uropathogenic bacteria, facilitating their aggregation and clearance from the urinary tract. Here, we present the cryo-electron microscopy (cryo-EM) structure of the bacteria-binding D10C domain of UMOD and reveal its binding to the filament core. The details of D10C-core binding explain the formation of distinct filament lattice architectures adopted by UMOD. The D10C-core binding interface gives rise to diverse filament lattice structures, ranging from open and expansive to compact and dense conformations, or a combination of both. We hypothesize that other molecules present in urine may act as cross-linking agents, further stabilizing this binding interface and facilitating the connection of individual filaments into larger networks capable of effectively trapping bacteria. Structural mapping of kidney disease-related mutations points toward the abolition of disulfide bonds and promotion of mutant UMOD aggregation. Structural basis of human uromodulin filament networks in uropathogen capture.,Chang AN, Cerutti G, Ogawa Y, Basler A, Switzer W, Eng-Kohn M, Lee C, Fitzpatrick AWP Structure. 2025 May 3:S0969-2126(25)00145-5. doi: 10.1016/j.str.2025.04.011. PMID:40345203[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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